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. 2020 Apr 6;33(9):804–812. doi: 10.1093/ajh/hpaa058

Figure 2.

Figure 2.

Mitophagy signaling pathways. (a) Parkin dependent mitophagy: healthy mitochondria import PINK1 via the translocase of the outer membrane (TOM) and translocase of the inner membrane (TIM) complexes. The mitochondrial targeting sequence is then cleaved off by the mitochondrial processing peptidase (MPP) and the inner mitochondrial membrane protease presenilin-associated rhomboid-like protease (PARL) cleaves PINK1. The resulting peptide is then retrotranslocated to the cytosol, where it is subjected to degradation via the proteasome. However, when mitochondria are damaged, PINK1 accumulates at the outer mitochondrial membrane bound to the TOM complex. As a result, PINK1 dimerizes and is activated by autophosphorylation. PINK1 subsequently phosphorylates Parkin and ubiquitin chains, resulting in Parkin activation and relocation to the mitochondria where it further ubiquitinates mitochondrial substrates and signals the removal of the damaged organelle. (b) Parkin-independent mitophagy: microtubule-associated protein 1A/1B light chain 3 (LC3) proteins anchored in the membrane of the phagophore can bind to LC3-interacting region (LIR) containing autophagic receptors (e.g., FUNDC1, BNIP3, and NIX) that are constitutively expressed on the outer membrane of mitochondria. Subsequently, the autophagosome can engulf the damaged mitochondria for degradation.